Fulvestrant, Formerly ICI 182,780, Is as Effective as
`Anastrozole in Postmenopausal Women With Advanced
`Breast Cancer Progressing After Prior Endocrine
`Treatment
`
`By A. Howell, J.F.R. Robertson, J. Quciresmci Albono, A. Aschermonnovci, L. Mciuricic, U.R. Kleeberg, I. Vergote,
`B. Erikstein, A. Webster, and C. Morris
`
`Purpose: To compare the efficacy and tolerability
`of fulvestrant (formerly ICI 182,780) and anastrozole
`in postmenopausal women with advanced breast
`cancer progressing after prior endocrine treatment.
`Patients and Methods: Patients (n = 451) with ad-
`vanced breast cancer were randomized to receive fulves-
`
`trant 250 mg as a once-monthly (one x 5 ml) intramus-
`cular iniection or an oral dose of anastrozole 1 mg in this
`open, parallel-group, multicenter trial. The primary end
`point was time to progression (TTP). Secondary end points
`included obiective response (OR) rates, defined as com-
`plete response (CR) or partial response (PR), duration of
`response (DOR), and tolerability.
`Results: Patients were followed for a median period
`of 14.4 months. In terms of TTP, fulvestrant was as
`effective as anastrozole (hazard ratio, 0.98; confidence
`interval [CI], 0.80 to 1.21; P = .84). Median TTP was 5.5
`months for fulvestrant and 5.1 months for anastrozole.
`
`OR rates showed a numerical advantage for fulvestrant
`(20.7%) over anastrozole (15.7%) (odds ratio, 1.38; CI,
`0.84 to 2.29; P = .20). Clinical benefit rates (CR + PR +
`stable disease 2 24 weeks) were 44.6% for fulvestrant
`and 45.0% for anastrozole. Median DOR was 15.0
`months for fulvestrant and 14.5 months for anastro-
`zole. Both treatments were well tolerated, with 3.2%
`and 1.3% of fulvestrant- and anastrozole-treated pa-
`tients, respectively, withdrawn from treatment because
`of an adverse event.
`Conclusion: Fulvestrant was as effective as anastro-
`zole. These data confirm that fulvestrant is an addi-
`tional, effective, and well-tolerated treatment for ad-
`vanced breast cancer
`in postmenopausal women
`whose disease progressed on prior endocrine therapy.
`J Clin Oncol 20:3396-3403. © 2002 by American
`Society of Clinical Oncology.
`
`HE TREATl\/[ENT OF breast cancer in postmeno-
`pausal women with horrnone-responsive tumors is
`based on two key approaches: prevention of estrogen
`binding to the estrogen receptor (ER) using an antiestrogen,
`or lowering of estrogen levels using an aromatase inhibitor.
`The selective estrogen receptor modulator tamoxifen (Nol-
`vadex, AstraZeneca Pharmaceuticals, Macclesfield, United
`Kingdom) is the most widely used hormonal treatment for
`breast cancer and has good efficacy in horrnone-sensitive
`tumors.1 Tamoxifen has also been shown to be highly
`
`From the Christie Hoqaital, Manchester, City Hospital, Nottingham,
`and Adrazeneca, Maoclesfield, Chediire, United Kingdom;
`lnstituto
`Portugues De Oncologia De Coirrbra, Coirrbra, Portugal; Odborny
`Lecebny Ustav Onkologie A Pne.im:>|ogie, Nova Ves Plod Plesi, Czech
`Republic;
`lnstitut Bergonie, Bordeaux, France; Haematologi$h/Onkolo-
`gisohe Praxis Harrburg, Germany; University Hospital Leuven, Leuven,
`Belgium; and Norwegian Radium Hospital, Oslo, Norway.
`aibmitted October 10, 2001; accepted April 22, 2002.
`aipported by a grant from Astrazeneca Pharmaceuticals
`This article was published ahead of print at vvvvw.joo.org.
`Address reprint requeststo A. Howell, MD, Department of Medical
`Oncology, Christie Hospital National Health Service Trust, Wllmslow
`Rd, Mancheder M20 4BX, United Kingdom; email (A.H.’sassistant):
`marla.parker@chridie-tr.nweS.nhsukto.
`© 2002 by American Society of Clinical Oncology.
`0732-1 83X/O2/201 6-3396/$20. 00
`
`effective in reducing the incidence of breast cancer in
`patients at high risk of developing the disease? Once breast
`cancer recurs or progresses after treatment with tamoxifen,
`standard follow-up treatments are the aromatase inhibitors,
`such as third—generation oral, selective aromatase inhibitors
`including anastrozole (Arimidex; AstraZeneca) or letrozole
`(Fernara', Novartis Pharma AG, Basel, Switzerland).
`A specific antiestrogen with high affinity for the ER and
`without agonist effects may have advantages over tamox-
`ifen in the treatment of horrnone-sensitive breast cancer.
`
`Fulvestrant (Faslodex, formerly known as ICI 182,780;
`Astra7.eneca) is a novel, steroidal, ER downregulator with a
`mode of action distinct from that of tamoxifen.3 Fulvestrant
`
`binds to the ER and a rapid loss of ER protein in the tumor
`ensues.4 This downregulation of the ER levels in the tumor
`is dose dependent, as is the significant reduction ir1 tumor
`progesterone receptor (PgR) levels.4 Tamoxifen, in contrast,
`is associated with a rise in PgR levels, which demonstrates
`the presence of a functional estradiol pathway and confirms
`the partial agonism of tamoxifen in contrast to the “pure”
`antagonist action of fulvestrant. Preclinical studies indicated
`that fulvestrant would be effective in tamoxifen-resistant
`
`breast cancer.5 A phase II trial conducted with fulvestrant in
`women with advanced breast cancer resistant to tamox-
`
`ifen6’7 demonstrated that fulvestrant has good clinical ac-
`tivity in tamoxifen-resistant breast cancer and also sug-
`
`3396
`
`Journal of Clinical Oncology, Vol 20, No l6 (August l5), 2002: pp 3396-3403
`DOI: lO.l 200/JCO.2002.l 0.057
`information downloaded from jco.ascopubs.org and provided by at UNIVERSITY NOTTINGHAM on October 17, 2014 from
`Copyright © 2002 American SOGIBB/2*9‘t’.IIlZir1Ma| Oncology. All rights resen/ed.
`
`AstraZeneca Ex. 2028 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01326
`
`

`
`COMPARISON OF FULVESTRANT AND ANASTROZOLE IN ADVANCED BREAST CANCER
`
`3397
`
`gested a prolonged duration of response (DOR) when
`compared indirectly with a matched group of patients who
`received megestrol acetate after failure of tamoxifen.7
`This article reports the results of an open, randomized,
`multicenter, parallel-group, phase III clinical
`trial
`that
`compared the efficacy and tolerability of fulvestrant 250 mg
`administered as a once-monthly intramuscular (IM) injec-
`tion with an oral dose of anastrozole 1 mg once daily, in
`postmenopausal women with advanced breast cancer whose
`disease had progressed after prior endocrine therapy.
`
`PATIENTS AND METHODS
`
`Study Desi gn
`
`This was an open, randomized, international, multicenter, parallel-
`group, phase III trial. It was originally designed to compare two doses
`of fulvestrant (125 mg and 250 mg per month IM) with a single dose
`of anastrozole (1 mg/d orally). The study (trial 0020) was carried out in
`Europe, Australia, and South Africa and involved 83 centers. In this
`open trial, fulvestrant 250 mg was given as a one >< 5-ml, injection,
`compared with the two >< 2.5-mL injections that were administered in
`the North American trial 0021. Trial 0021 was a double-blind,
`double—dummy trial using the same drug doses and a similar protocol
`that ran concurrently, also appearing in the August 15, 2002, issue of
`the Journal of Clinical OnC0logy.8 These trials were designed to be
`evaluated individually and using combined data.
`A preliminary data summary and an interim analysis were planned
`and conducted because the clinical activity of fulvestrant 125 mg had
`not been previously tested. Therefore, both trials included a preliminary
`data summary stage after the first 30 subjects in the fulvestrant 125-mg
`group (combined from both trials) had been treated and followed up for
`a minimum of 3 months. This interim assessment showed insufficient
`evidence of clinical activity for the 125-mg dose of fulvestrant, with no
`objective tumor responses. The independent data monitoring commit-
`tee therefore recommended that recruitment to the fulvestrant 125-mg
`treatment arm be stopped. Patients already recruited into the 125-mg
`arm in this trial were permitted to remain on fulvestrant 125 mg or be
`withdrawn from the trial and returned to other treatments at the
`discretion of their clinician. These patients were not monitored further
`for efficacy. As a consequence of dropping this treatment arm, the
`protocol for the study was amended to be a comparison between
`fulvestrant 250 mg (IM) and anastrozole 1 mg/d orally.
`An interim analysis was conducted when 170 disease progressions or
`deaths had occurred across the remaining arms and time to progression
`(TTP) was formally analyzed. Objective response (OR) rate (defined as
`complete response [CR] + partial response [PR], using Union Inter-
`nationale Contre le Cancer criteria) and adverse event (AE) data were
`summarized. As a result of the interim analysis, the independent data
`monitoring committee recommended that both trials should continue.
`Fulvestrant 250 mg (IM) was compared with anastrozole (1 mg/d
`given orally) in terms of the primary end point of TTP. Secondary
`end points included OR, DOR, time to treatment failure (TTF), time
`to death (TTD), and tolerability. Other secondary end points were
`quality of life, symptomatic response, and pharmacokinetics. Other
`efficacy datapoints reported included clinical benefit (CR + PR +
`stable disease [SD] 2 24 weeks), and duration of clinical benefit.
`All data are reported here except for pharmacokinetics, which will
`be reported elsewhere.
`
`Patient Population
`
`All patients were postmenopausal women with locally advanced or
`metastatic breast cancer whose disease had progressed during adjuvant
`endocrine therapy or first-line endocrine therapy for advanced disease.
`All women had tumors with evidence of hormone sensitivity (ie, prior
`sensitivity to hormonal therapy or known ER or PgR positivity) and life
`expectancy of greater than 3 months, and in the opinion of the
`investigator, all were deemed appropriate candidates for subsequent
`hormonal therapy.
`For inclusion in the trial, patients had to have a World Health
`Organization performance status of S 2, histologic or cytologic
`confirmation of breast cancer, and objective evidence of recurrence or
`progression of disease that was not amenable to curative treatment,
`with the presence of at least one measurable or assessable (nonmea-
`surable) lesion. All patients had to be postmenopausal (ie, 2 60 years
`old or aged 2 45 years with arnenorrhea for > 12 months or
`follicle-stimulating hormone levels within postmenopausal range, or
`having undergone bilateral oophorectomy).
`Exclusion criteria included the following: presence of life-threaten-
`ing metastatic visceral disease (defined as extensive hepatic involve-
`ment) or any degree of brain or
`leptomeningeal
`involvement or
`symptomatic pulmonary lymphangitic spread; prior treatment for breast
`cancer with fulvestrant or any aromatase inhibitor; more than one
`prior endocrine treatment for advanced breast cancer; extensive
`radiation therapy or cytotoxic treatment within the past 4 weeks;
`estrogen replacement therapy within 4 weeks of randomization;
`treatment with luteinizing hormone—releasing hormone analogs
`within 3 months of randomization; and any concurrent medical
`illness or laboratory abnormalities that would compromise safety or
`prevent interpretation of results.
`Subjects taking bisphosphonates were permitted to enter the trial but
`their bone lesions were not considered to be assessable for response,
`although they were assessable for progression. Initiation of bisphos-
`phonate treatment during the trial was discouraged. If bisphosphonates
`were commenced in the absence of objective evidence of progression,
`bone lesions were assessed only for progression.
`All patients gave written informed consent, and approval was
`obtained from the relevant ethical committees.
`
`Trial Treatments
`
`Fulvestrant was supplied in vials as a single-dose, castor oil—based,
`5% solution. Each vial contained 250 mg of fulvestrant at a concen-
`tration of 50 mg/mL in a volume of 5 mL. Fulvestrant 250 mg was
`administered slowly by a single one >< 5-mL injection into the buttock.
`Injections were given once a month, which was defined as every 28
`days (: 3 days). Anastrozole 1 mg was supplied as round, white,
`film-coated tablets and administered orally once daily.
`Patients continued treatment until objective disease progression or
`other events required withdrawal. At such time, trial treatment was
`stopped and standard therapy was initiated. Thereafter, patients were
`followed up until death. Patients who withdrew from trial treatment
`before disease progression were followed up until objective disease
`progression and death.
`For all patients, objective tumor assessments were undertaken every
`3 months until evidence of either objective disease progression or
`death. Patients with skin or soft tissue lesions were also assessed every
`month during the first 3 months of treatment.
`
`Information downloaded from jco.asoopubs.org and provided by at UNIVERSITY NOTTINGHAM on October 17, 2014 from
`Copyright © 2002 American SoG®a5/Zzfrilziniial Oncology. All rights reserved.
`
`AstraZeneca Ex. 2028 p. 2
`
`

`
`3398
`
`Sati Si cal Methodology
`
`The trial was designed to detect the superiority of fulvestrant 250
`mg in terms of efficacy compared with anastrozole 1 mg. The final
`analysis was scheduled to occur when 340 events (ie, objective
`disease progression or death) had occurred across the two groups.
`This provided 90% power to detect a hazard ratio (HR) 2 1.43 or S
`0.70 for fulvestrant treatment compared with anastrozole treatment,
`at a significance level of 5%. To achieve the required number of
`events, it was calculated that 392 patients (196 in each treatment
`group) would be required.
`The efficacy analyses were performed according to randomized
`treatment (ie, “intention to trea ”) using a nominal significance level
`of 5%. However, for the TTP and OR analyses, the significance
`level was adjusted to 4.86% because of the preliminary data
`summary of OR and the interim analysis of TTP. As a result, the
`95% confidence intervals
`(CIs) were adjusted accordingly to
`95.14%. All significance levels were two-sided.
`Although not described in the protocol, fulvestrant was retrospec-
`tively compared with anastrozole for noninferiority for OR, TTP and
`TTF. Because of the interim analysis, a one-sided CI of 97.57% was
`used for the analyses of TTP and OR. For TTF, a one-sided CI of
`97.5% was used. These limits are identical to using the upper limit of
`the 95.14% two—sided CI from the analysis of TTP, the lower limit of
`the 95.14% two—sided CI for the difference in response rates for OR,
`and the upper limit of the 95% two—sided CI for TTF.
`For previous United States regulatory submissions of hormonal
`treatments for advanced breast cancer, the requirements for showing
`noninferiority for TTP were based on the upper one-sided confidence
`limit for the TTP HR not being greater than 1.25 (ie, a potential
`deficiency of > 25% for the experimental treatment had to be ruled
`out).
`In the same submissions,
`the requirement for demonstrating
`noninferiority in terms of response rate was based on ruling out a
`deficiency in the difference in response rates of greater than 10%.
`Consequently, these criteria have been used to assess noninferiority of
`fulvestrant relative to anastrozole in this trial.
`'|'|'P. TTP was defined as the time from randomization until
`objective disease progression. Death was regarded as a progression
`event in those Who died before disease progression. Subjects whose
`disease had not progressed at the time of analysis were right-censored
`using the last assessment date. Treatments were compared using the
`Cox proportional hazards regression model (including the covariates
`age, performance status, measurable compared with nomneasurable
`disease, receptor status, previous response to hormone therapy, previ-
`ous use of cytotoxic chemotherapy, and use of bisphosphonate therapy
`for bone disease). A global test was performed to determine whether
`there were significant treatment-by-baseline covariate interactions. The
`estimate of the treatment effect is expressed as an HR (fulvestrant/
`anastrozole), together with the corresponding CI and P value. TTP was
`also summarized using Kaplan-Meier curves for each treatment group,
`and the median TTP was calculated.
`'|'|'F. TTF was defined as the number of days from randomization
`until the earliest occurrence of disease progression, death from any
`cause, or withdrawal from trial treatment for any reason. Patients who
`had not experienced treatment failure at the time of analysis were
`right-censored in the analysis at the time of their last assessment. Any
`patient who did not receive any trial therapy was assigned an uncen-
`sored TTF of zero days. Statistically, TTF was analyzed in the same
`Way as TTP.
`OR rate.
`Responders were defined as those patients with CR or PR.
`To qualify as a responder, the patient had to satisfy the criteria for CR
`
`HOWELL ET AL
`
`or PR on one visit with no evidence of disease recurrence or death
`within 4 weeks of the response assessment. Treatment differences in
`OR were assessed by comparing the proportion of responders (CR and
`PR) using a logistic regression model (with the same covariates as for
`TTP). The estimate ofthe treatment effect is expressed as an odds ratio
`(fulvestrant/anastrozole), together with the corresponding CI and P
`value.
`In addition, an estimate of the difference in response rates
`(fulvestrant/anastrozole) and corresponding CI was also produced?
`DOR. The DOR was defined, for responding patients only, as the
`period of time from randomization to the first observation of disease
`progression. Patients who died before reaching progression were
`classed as completing their response at time of death. The DOR was
`summarized using Kaplan-Meier curves for each treatment group, and
`the median DOR was also calculated for each group.
`No statistical comparison was performed for DOR in only those
`patients responding to treatment, since this is not a randomized
`comparison. Rather, all patients were included in a statistical analysis
`of DOR, defined for responders as the time from the onset of response
`to disease progression and for nonresponders as zero. These data were
`also summarized using Kaplan-Meier curves.
`Clinical benefit. Clinical benefit was defined by the sum of CR +
`PR + SD 2 24 weeks. Although a formal analysis of clinical benefit
`was not protocoled, treatment differences in the rate of clinical benefit
`were retrospectively assessed in the same way as that of OR rate. The
`duration of clinical benefit was presented as for DOR.
`'|_|'D. TTD was protocoled to be analyzed when at least 50% of
`the patients had died. At the time of data analysis, only 36.7% of
`patients had died and therefore no formal statistical analyses were
`made at this time.
`
`Tolerability
`Any detrimental change in a patient’s condition subsequent to them
`entering onto the trial and during the follow-up period after the final
`treatment (8 weeks after last injection of fulvestrant and 30 days after
`the last day of treatment with anastrozole), which was not unequivo-
`cally due to progression of disease, was considered to be an AE. All
`safety data were listed and summarized according to the treatment
`received. No formal statistical analyses were performed on the safety
`data from this individual trial. However, a planned statistical analysis
`of predefined AEs was performed on the combined data from this trial
`and the North American trial; this will be reported elsewhere. The most
`common AEs (occurring at incidence of 2 10%) and most common
`drug-related AEs are reported here by t1eat1I1e11t received.
`
`Quality of Life
`Quality of life (QOL) was assessed using the Functional Assessment
`of Cancer Therapy (FACT)—Breast questionnaire, which comprises the
`FACT-General QOL tool for cancer patients plus the breast cancer
`subscale. This questionnaire has been extensively validated in respect
`to its psychometric properties and sensitivity to clinical changes1°’”
`am:
`is in use in a number of large breast cancer treatment trials in the
`United States and Europe.
`"he analysis was undertaken on data collected up to the date of
`progression, using the trial outcome index (TOI) within the FACT-
`Breast. This measure is the sum of the functional well-being, physical
`we l—being and breast cancer subscale dimensions of the questionnaire.
`Patients without baseline TOI data or with data collected more than 7
`days after the start of treatment were excluded from this analysis.
`"he difference in TOI over time between the fulvestrant 250-mg
`group and the anastrozole l—mg group was compared using a general-
`
`Information downloaded from jco.asoopubs.org and provided by at UNIVERSITY NO‘|‘|'|NGHAM on October 17, 2014 from
`Copyright © 2002 American SoG®a5/2;fIIZir1iEa| Oncology. All rights reserved.
`
`AstraZeneca Ex. 2028 p. 3
`
`

`
`COMPARISON OF FULVESTRANT AND ANASTROZOLE IN ADVANCED BREAST CANCER
`
`3399
`
`Characteristic
`
`Age, years
`Mean
`Range
`Weight, kg
`Mean
`Range
`Prior treatment
`
`Cytotoxic chemotherapy
`Endocrine therapy for advanced disease
`Adiuvant endocrine therapy
`Hormone receptor status
`ER and/or PgR+ve
`ER/PgR unknown
`ER/PgR-ve
`Metastatic or recurrent disease at baseline
`Breast
`Skin
`Bone
`Liver
`Lung
`Lymph nodes
`Other
`Extent of metastatic or recurrent disease at
`baseline
`Soft tissue only
`Bone only
`Visceral only
`Lymph node only
`Not recorded
`Mixed”
`Measurable lesions‘l'
`Nonmeasurable lesions
`
`Table 1. Demographic and Pretreatment Characteristics
`Fulvestrant 250 mg (n : 222)
`
`No.
`
`%
`
`63
`35-86
`
`69
`41-124
`
`42.3
`56.8
`54.5
`
`73.4
`23.0
`3.6
`
`9.5
`18.0
`51.8
`21 .6
`25.2
`35.1
`1 2.2
`
`5.0
`17.1
`13.5
`9.9
`O
`54.5
`59.0
`41 .0
`
`94
`126
`121
`
`163
`51
`8
`
`21
`40
`115
`48
`56
`78
`27
`
`11
`38
`30
`22
`0
`121
`131
`91
`
`Anastrozole 1 mg/cl (n : 229)
`No.
`
`%
`
`64
`33-89
`
`68
`40-110
`
`98
`129
`119
`
`183
`37
`9
`
`30
`35
`117
`56
`60
`83
`18
`
`8
`40
`41
`21
`1
`118
`142
`87
`
`42.8
`56.3
`52.0
`
`79.9
`16.2
`3.9
`
`13.1
`15.3
`51.1
`24.5
`26.2
`36.2
`7.9
`
`3.5
`17.5
`17.9
`9.2
`0.4
`51.5
`62.0
`38.0
`
`NOTE. Patients may be in more than one category.
`Abbreviations: ER, estrogen receptor; PgR, progesterone receptor.
`‘Mixed is defined as breast and/or a combination of skin, bone, liver, lung, or lymph nodes.
`‘l'MeasUrable lesions were lesions that were clinically measurable in two perpendicular axes with at least one dimension being 2 2.5 cm or measurable using
`imaging in two perpendicular axes with at least one dimension being 2 1.0 cm.
`
`ized linear mixed model (ie, a random coefficients model) with the
`same covariates as for TTP. A graph of the mean TOI (i standard
`deviation) over time was also produced.
`
`RESULTS
`
`Pati ents
`
`A total of 451 patients were randomized to fulvestrant 250
`mg (n = 222) or to anastrozole 1 mg once daily (n = 229) and
`were followed for a median period of 14.4 months. "he
`majority of patients (97% in the fulvestrant group and 98% in
`the anastrozole group) had previously been treated with tamox-
`ifen as either adjuvant therapy or for advanced disease. "he
`other patients were previously treated with droloxifene, gos-
`erelin, idoxifene, megestrol acetate, or toremifene. A total of
`
`95 patients in the fulvestrant group and 100 patients in the
`anastrozole group had only received endocrine therapy as
`adjuvant treatment. Of these, the majority (80.0%) stopped
`treatment less than 365 days before randomization.
`The characteristics of the patients in the two treatment
`groups are given in Table 1. Patients in the fulvestrant and the
`anastrozole groups were well matched in terms of age, weight,
`breast cancer history, and ER/PgR status. Only 11.8% of
`patients in the fulvestrant group and 7.5% of patients in the
`anastrozole group had bisphosphonate therapy.
`
`Efficacy
`
`TTP. At the time of analysis, 183 (82.4%) of 222 of
`those patients randomized to fulvestrant had progressed, as
`
`Information downloaded from jco.asoopubs.org and provided by at UNIVERSITY NOTTINGHAM on October 17, 2014 from
`Copyright © 2002 American SoG®i5/2;fIIZir1iEaI Oncology. All rights reserved.
`
`Astrazeneca Ex. 2028 p. 4
`
`

`
`3400
`
`1.0
`
` 0.9
`
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`
`
`
`
`
`Proportionwithoutprogression 0.1
`
`Median ‘|‘|'P: Fulvestrant
`Anastrozole
`
`5.5 months
`5.1 months
`
`HOWELL ET AL
`
`
`
`4.6 months
`Median TTF: Fulvestrant
`Anastrozole 4.1 months
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`
`0.1
`
`
`
`Proportionnotfailing
`
`Fulvestrant 250 mg
`
`—————--— Anastrozolei mg
`
`0
`
`2
`
`4
`
`6
`
`B
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`
`
`I
`26
`
`T‘“‘=\_
`Fulvestrant 250 mg
`————— - — Anastrozole 1 mg
`
`
`
`
`0
`2
`4
`6
`8
`10
`12
`14
`16
`13
`20
`22
`24
`26
`Time to progression (months)
`
`Time to treatment failure (months)
`
`Fig 1. Kaplan-Meier estimates for time to progression.
`
`Hg 2. Kaplan-Meier estimates for time to treatment failure.
`
`had 191 (83.4%) of 229 of those randomized to anastrozole.
`The statistical analysis showed that there was no evidence
`of a statistically significant difference in TTP between
`fulvestrant and anastrozole (HR, 0.98‘, 95.14% CI, 0.80 to
`1.21‘, P = .84). The 95.14% C1 indicates that the risk of
`progression for patients randomized to fulvestrant 250 mg
`could be between 20% lower and 21% higher than it is for
`patients randomized to anastrozole. These data fulfill the
`criteria for noninferiority of fulvestrant relative to anastro-
`zole. The Kaplan-Meier curves for TTP with fulvestrant and
`anastrozole are shown in Fig 1. The median TTP was 5.5
`months for fulvestrant and 5.1 months for anastrozole.
`
`TTF. At the trial cutoff date, 188 patients (84.7%) in the
`fulvestrant group and 196 patients (85.6%) in the anastro-
`zole group had experienced treatment failure. The statistical
`analysis showed that fulvestrant was not significantly dif-
`ferent from anastrozole in terms of TTF (HR, 0.97; 95% Cl,
`0.80 to 1.19‘, P = .81)
`(Fig 2), and the criteria for
`noninferiority of fulvestrant were fulfilled. The median TTF
`was 4.6 months for fulvestrant and 4.1 months for anastro-
`
`zole. Of those patients whose treatment failed. 94.7% of the
`fulvestrant group and 95.4% of the anastrozole group
`experienced treatment failure because of disease progres-
`sion. Other reasons for treatment failure included AES
`
`(fulvestrant V anastrozole, 1.6% V 1.5%), protocol noncom-
`pliance (1 . 1% V 2.0%), and withdrawal of informed consent
`(1.1% V 0.5%).
`OR rate. At the time of data cutoff, 20.7% of patients in
`the fulvestrant group and 15.7% of those in the anastrozole
`group had evidence of OR (ie, had a best OR of CR or PR)
`(Table 2). The statistical analysis for OR showed no
`statistically significant difference between fulvestrant and
`anastrozole (difference in response rates, 4.8%‘, 95.14% CI,
`-2.19%, to 14.23%), and the criteria for noninferiority of
`fulvestrant were fulfilled. There was a nonsignificant nu-
`merical advantage for fulvestrant over anastrozole, with the
`
`odds of attaining OR being 38% higher in the fulvestrant
`group (odds ratio, 1.38‘, 95.14% CI, 0.84 to 2.29; P = .20).
`Clinical benefit rates (CR + PR -1- SD 2 24 weeks) of
`44.6% and 45.0% were observed for fulvestrant and
`
`anastrozole, respectively (Table 2), with the analysis
`showing no statistically significant difference (difference
`in clinical benefit rates, -0.95%‘, 95% C1, -10.12% to
`8.64%; P = .85).
`Further follow-up was performed to obtain more com-
`plete
`information for DOR (median follow-up, 22.6
`months). The median DOR, as measured from randomiza-
`tion to progression,
`in those patients who responded to
`treatment was 15.0 months for fulvestrant (n = 48) and 14.5
`months for anastrozole (n = 39). Kaplan-Meier curves for
`
`Table 2. Best Obiective Responses for Fulvestrant, 250 mg IM or
`Anastrozole 1 mg Orally ocl
`Fulvestrant
`(n : 222)
`
`Anastrozole
`in : 229)
`
`CR
`PR
`Total (OR)
`SD 2 24 Weeks
`SD < 24 weeks
`
`Not progressecl‘l'
`Progressecl
`Total
`Clinical loenelit (CR + PR +
`SD 2 24 weeksl
`
`No.
`10
`36
`46
`53
`3
`
`10
`110
`176
`99
`
`%
`4.5
`16.2
`20.7‘
`23.9
`1.4
`
`4.5
`49.5
`79.3
`44.61
`
`No.
`4
`32
`36
`67
`3
`
`6
`117
`193
`103
`
`"/0
`1 .7
`14.0
`15.7
`29.3
`1.3
`
`2.6
`51.1
`84.3
`45.0
`
`Abbreviations: CR, complete response; PR, partial response; SD, stable
`disease.
`*Dillerence in response rates, 4.8%; 95.14% Cl, -2.19% to 14.23%.
`'l'Patients with a loest response ol "not progressed" were not assessable lor
`response except lor progression (eg, patients with bone-only disease taking
`bisphosphonates].
`TDillerence in clinical loenelit rates, -0.95%; 95% Cl, -10.12% to 8.64%;
`P : .85.
`
`Information downloaded from jco.asoopubs.org and provided by at UNIVERSITY NOTTINGHAM on October 17, 2014 from
`Copyright © 2002 American So11®t5/Zofriiziniial Oncology. All rights reserved.
`
`AstraZeneca Ex. 2028 p. 5
`
`

`
`COMPARISON OF FULVESTRANT AND ANASTROZOLE IN ADVANCED BREAST CANCER
`
`3401
`
`Median DOCB: Fulvestrani 11.7 months
`Anastrozole 11.4 months
`
`
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0
`
`
`
`Proportionresponding
`
`Median DOR: Fulvestrant 15.0 months
`
`Anastrozole 14.5 months
`
`: Fulvestrant 250 mg
`
`- -
`' Anastrozole 1 mg
`0
`2
`4
`6
`8 1012 1416 18202224262B3032 34363840
`Duration of response (months)
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`
`
`
`
`
`Proportionwithclinicalbenefit
`
`.4 Fulvestram250mg
`
`— -
`2
`0
`
`- Anastrozo|e1 mg
`4
`5 8101214161B2022242B28303234363840
`Duration of clinical benefit (months)
`
`
`
`Fig 3. Kaplan-Meier estimates for duration of response (responding
`patients only).
`
`Fig 5. Kaplan-Meier estimates for duration of clinical benefit (DOCB).
`
`DOR with fulvestrant and anastrozole are shown in Fig 3. In
`addition, DOR using all patients—where DOR was defined
`as from the onset of response to disease progression for
`responders and as zero for nonresponders—was signifi-
`cantly greater for fulvestrant compared with anastrozole
`(ratio of average response durations, 1.27‘, 95% Cl, 1.05 to
`1.55‘, P = .01‘, Fig 4). The median duration of clinical
`benefit was 11.7 months in the fulvestrant group (n = 100)
`and 11.4 months in the anastrozole group (n = 104; Fig 5).
`'|'|'D. As specified in the protocol, TTD (overall sur-
`vival) will be analyzed when more than 50% of the patients
`have died. At the time of this data analysis, 82 patients
`(36.9%) in the fulvestrant group and 83 patients (36.2%) in
`the anastrozole group had died‘, therefore, no formal statis-
`tical analyses have been conducted. The formal analysis of
`TTD will be presented in a future publication.
`
`Tolerability
`
`Both fulve strant and anastrozole were well tolerated, with
`only seven fulvestrant patients (3.2%) and three anastrozole
`patients (1.3%) withdrawn because of AEs. A wide range of
`AEs was reported by patients in both treat111e11t groups,
`mostly of mild to moderate intensity. The incidence of side
`
`effects considered important with endocrine therapy (ful-
`vestrant V anastrozole), such as weight gain (0.5% V 1.7%),
`thromboembolic events (3.7% V 1.7%), and vaginitis (1.8%
`V 1.3%), was low in both treatment groups. The incidence of
`joint disorders including arthralgia was lower in the fulves-
`trant-treated group than in the anastrozole-treated group
`(1.4% V 8.3%). The most frequently reported AEs and the
`most common drug-related AEs are shown in Tables 3 and
`4, respectively.
`The 219 patients treated with fulvestrant received a
`total of 1,898 injections. Sixteen patients (7.3%) in the
`fulvestrant treatment group reported injection site AEs
`(comprising injection site pain,
`inflammation, hemor-
`rhage, hypersensitivity, and reaction). Only 20 injections
`out of the total of 1,898 (1.1%) resulted in an injection
`site event. All of these events were of mild intensity and
`nonserious, and only one patient with an injection site
`event withdrew from the trial.
`
`QOL
`
`A graph of the mean TOI (i standard deviation) over
`time is shown in Fig 6. Analysis of QOL data up to disease
`progression showed that the QOL was maintained over time
`
`
`
`Proportionresponding
`
`
`
`Ratio of average response durations 1.27
`(95% CI, 1.05 to 1.55; P = .01)
`
`0.35
`.0ca
`0.25
`.0i\)
`0.15
`.0
`
`
`
`0.05 —— Fulvestrant 250 mg
`— -
`- Anastrozole 1 mg
`0
`2
`4
`6 B10121416182022242628303234363840
`Duration of response (months)
`
`0
`
`Table 3. Most Common Adverse Events Occurring in 2 10% of Patients
`Fulvesirant [n : 219)
`Anostrozole (n : 230)
`No
`%
`No.
`%
`
`Nausea
`Vasoolilatalion
`Asthenia
`Vomiting
`Bone pain
`Pharyngitis
`Constipation
`Headache
`Pain
`
`48
`35
`33
`28
`28
`26
`23
`22
`21
`
`21 .9
`16.0
`15.1
`1 2.8
`12.8
`1 1 .9
`1 0.5
`10.0
`9.6
`
`42
`30
`43
`18
`26
`13
`17
`25
`28
`
`18.3
`13.0
`18.7
`7.8
`11.3
`5.7
`7.4
`10.‘?
`1 2.2
`
`Fig 4. Kaplan-Meier estimates for duration of response (all patients).
`
`Information downloaded from jco.asoopubs.org and provided by at UNIVERSITY NO‘|‘|'|NGHAM on October 17, 2014 from
`Copyright © 2002 American some/zxrmnizai Oncology. All rights reserved.
`
`AstraZeneca Ex. 2028 p. 6
`
`

`
`3402
`
`HOWELL ET AL
`
`Table 4. Most Common Drug-Related Adverse Events (excluding injection
`site events) Occurring in 2 2% of Patients
`Fulvestrant (n : 219)
`Anastrozole (n : 230)
`No.
`%
`No.
`%
`
`Vasodilatation
`Nausea
`Sweating
`Headache
`Asthenia
`Anorexia
`
`26
`19
`6
`6
`5
`2
`
`1 1 .9
`8.7
`2.7
`2.7
`2.3
`0.9
`
`29
`20
`8
`7
`1 1
`9
`
`12.6
`8.7
`3.5
`3.0
`4.8
`3.9
`
`—Et— Fulvestrant
`‘ "' Anastrozole
`
`
`
`
`
`Meantreatmentoutcomeindex(TOI)
`
`
`
`
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`and that the treatments